Chronic lymphocytic leukemia therapy: new targeted therapies on the way

Introduction: The critical role of the tissue microenvironment and B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) pathogenesis, and the clinical success of targeted agents that disrupt BCR signaling are currently changing the CLL landscape. Three new drugs were recently approved for CLL therapy, and other agents are in late development.

Areas covered: In this review, we summarize data on promising new targeted drugs for CLL. The heterogeneous mechanisms of actions of these molecules are described, such as the inhibition of BCR signaling, direct targeting of CD20 molecules on the CLL cell surface, and BCL-2 inhibition. We present preclinical and clinical data from phase I to III studies in order to describe efficacy and side effect profile of these new drugs. Data are derived from peer-reviewed articles indexed in PubMed and from abstracts presented at major international meetings.

Expert opinion: Ibrutinib and idelalisib are challenging the role of chemo-immunotherapy in CLL therapy in the frontline and relapsed disease settings. High-risk CLL patients particularly benefit from these new agents. Venetoclax and obinutuzumab are other effective agents added to our therapeutic armamentarium. Studies to better define the optimal use of these drugs, alone, or rather in combination or sequenced are underway.     

The impact of epigenomics on future drug design and new therapies

The future of drug design and the development of new therapeutics will rely on our ability to unravel the complexities of the epigenome in normal and disease states. Proper epigenetic regulation is essential for normal differentiation in embryogenesis and development. Conversely, abnormal epigenetic regulation is a feature of complex diseases, including cancer, diabetes, heart disease and other pathologies. Epigenetic therapies hold promise for a wide range of biological applications, from cancer treatment to the establishment of induced pluripotent stem cells. The creation of more specific and effective epigenetic therapies, however, requires a more complete understanding of epigenomic landscapes. Here, we give a historical overview of the epigenomics field and how epigenetic modifications can affect embryo development and disease etiology. We also discuss the impact of current and future epigenetic drugs.     

Myeloproliferative neoplasms: new translational therapies

The myeloproliferative neoplasms represent a diverse group of hematologic malignancies that have been the subject of intense investigation over the last decade. Although clinical trials of the much anticipated small molecule inhibitors of Janus kinase 2 have shown that these experimental agents are successful in palliating many of the symptoms associated with the myeloproliferative neoplasms, they have not been reported to affect the disease initiating hematopoietic stem cell population or to alter the natural history of these disorders. Investigators remain optimistic that new information about the genetic and cellular origins gained from the efforts of numerous laboratories will ultimately translate in to the identification of new drug targets and more effective therapies. We hypothesize that ultimately, the use of combinations of drugs including chromatin modifying agents, immunomodulatory agents, anti-apoptotic agents, cellular therapies and monoclonal antibodies will be required to effectively treat patients with myeloproliferative neoplasms.     

Malignant gliomas: new translational therapies

Malignant gliomas are the most common primary brain tumors in adults and carry a dismal prognosis. Despite aggressive therapy with maximal safe surgical resection, radiation and chemotherapy, these tumors invariably are refractory to or become resistant to treatment and recur. Gliomas are highly infiltrative cancers and display remarkable genetic heterogeneity making them challenging to treat. Recent progress has been made in understanding the molecular and genetic composition of these tumors and from this, promising new targets for therapy have emerged. In particular, anti-angiogenesis therapies have led to modest success in disease control. In addition, the growing body of research in cancer immunology as well as cancer stem cells has made inroads in our understanding of tumorgenesis. Translational research has been particularly crucial to the development of these therapies as much preclinical and clinical work is needed to develop the rationale for treatments, to develop biomarkers of drug activity and to elucidate mechanisms of resistance. This brief overview will discuss some of the pivotal advances made in the pursuit of improved outcomes and survival for patients with this devastating disease.     

Gene therapy: future strategies and therapies

Significant advances have been made in the past decade concerning the mechanistic basis for the control of penile erection and the etiology of erectile failure. The combined efforts and accumulated wisdom of urologic scientists and clinicians around the world have ensured that these basic advances have translated into the remarkable success recently observed in the treatment of erectile dysfunction. In fact, erectile function can now be effectively restored in every man with the requisite level of desire and motivation. Nonetheless, all of the currently available treatment options have either limited efficacy, significant and untoward side effects, or both. There is clearly room for improvement. However, improved therapy of erectile dysfunction is dependent on garnering even more precise details concerning the regulation of human corporal smooth muscle tone, and furthermore, on the identification of relevant molecular targets. The next generation of erectile dysfunction therapies, therefore, will necessarily require the application of molecular technologies to the study of erectile physiology/dysfunction. One such application is the utilization of gene therapy approaches. This report outlines the overall goals and promise of gene therapy for the treatment of human erectile dysfunction and briefly reviews a few initial strategies to that end.     

Functional genomics: from genes to new therapies

The application of genomics in pharmaceutical R&D is presently one of the central issues in the industry. The evolution of functional genomics approaches and their integration into a technology platform for therapeutic discovery is a challenging and complex process. In this review, the authors describe how functional genomics will offer significant opportunities in the search for causal and disease-modifying therapies for better treatment of society’s most outstanding medical needs.     

Adult atopic dermatitis: new and emerging therapies

Introduction: Adult atopic dermatitis (AD) is very difficult to manage. Indeed, AD in adults is frequently refractory to topical treatment, especially with regards to the persistent form. Therefore, long-term treatment with oral immunosuppressive therapy is often required to control the burden of the disease, prevent ?are-ups and achieve better patient quality of life outcomes.

Areas covered: In the last decade the better understanding of AD pathogenesis has been used to improve treatment strategies with many emerging therapeutics options. Epidermal barrier impairment often plays the initial role in the initiation of the disease. Moreover, T helper 2 cytokines interleukin (IL)-4 and IL-13 and their downstream effects are prominent in AD, with pleiotropic effects on the innate and adaptive immune system. Targeting these cells, their products or receptors appears to be a reasonable therapeutic strategy.

Expert commentary: In the next years, many therapeutic options for adult AD will be available. Clinical trials showed that JAK inhibitors, PDE-4 inhibitors and monoclonal antibodies against some IL (IL-4, IL 13, IL-17, IL-22, IL-31) seem to be the most promising drugs, but dermatologists will have to evaluate their effectiveness and safety in clinical practice.     

慢性阻塞性肺疾病急性加重期的抗菌治疗

<正>关于慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)急性加重的诊断标准尚缺乏统一的认识,通常认为是在疾病过程中,患者短期内出现咳嗽、咳痰、气短和(或)喘息加重,痰量增多,呈脓性或黏脓性,可伴发热等炎症明显加重的表现。     

Etidronic acid and steroid therapy: new indication. No proven impact on fractures

(1) Etidronic acid (disodium etidronate) has a new licensed indication in the prevention of bone loss due to steroid therapy. (2) Three randomised, double-blind placebo-controlled trials have been done in this setting. The benefit of etidronic acid has been shown only on the basis of lumbar bone density (a surrogate end point) and only in women. (3) There is no concrete evidence that etidronic acid is any more effective than a placebo in reducing the risk of fracture in patients on steroid therapy. Similarly, in the absence of comparative trials there is no proof that etidronic acid is any more effective than hormone replacement therapy in postmenopausal women.     

Chemokine receptors: emerging opportunities for new anti-HIV therapies

The chemokine receptors CCR5 and CXCR4 are G-protein coupled receptors (GPCRs) of the immune system and the major co-receptors required for entry of HIV into CD4(+) target cells. CCR5 is critical for both human immunodeficiency virus (HIV) disease transmission and progression, whereas CXCR4 may be very important in late stages of disease. Additional co-receptors have been shown to function under certain conditions in vitro but evidence of supporting roles in HIV disease is currently lacking. The sheer number of co-receptors potentially used by HIV and the complexity of co-receptors usage are major challenges confronting usage of these molecules as drug development targets. Balanced against this, is a long history of success by the pharmaceutical industry in developing small molecule antagonists for many other classes of GPCRs. In this review, we discuss the current state of understanding of the co-receptor-based antiviral agents designed to block viral entry. The therapeutic potential of this field will be judged from future studies on the efficacy of these novel inhibitors in clinical trials. The data so far obtained from a number of studies point to the potential clinical use of this emerging class of therapeutic agents. Here we review current progress in co-receptor-based antiretroviral drug development and discuss the potential advantages and disadvantages of this approach.     

Perspectives of new therapies for endometriosis

Endometriosis is an inflammatory disease characterized by the presence of endometrial glandular epithelial and stromal cells growing in the extra-uterine environment. The disease affects: ovarian function, oocyte quality, embryo development and implantation, and uterine function resulting in infertility or spontaneous pregnancy loss. Even though the world's prevalence is above 10 %, an effective treatment has not yet been found. New pharmacological approaches have been designed and patented that could serve as future therapies for this disease.     

Antipsoriatic drug development: challenges and new emerging therapies

Psoriasis is a chronic recurring skin disorder affecting up to 2% of the world's population. Psoriatic lesions are generally visible, leading to significant emotional and social disabilities for patients. In the context of psoriasis, the orchestrated interplay between activated T cells, antigen-presenting cells and keratinocytes leads to the release of proinflammatory cytokines, chemokines and chemical mediators responsible for the perpetuation of this disease. Even though some therapies are available for psoriasis treatment, there is still no cure for this skin disorder and psoriatic patients are significantly unsatisfied, as demonstrated by recent worldwide surveys. Unlike other diseases, psoriasis does not have a generally accepted animal model, which complicates the successful introduction of new antipsoriatic drugs into clinical phases of development. Moreover, psoriasis affects infants, children and elderly patients which require long-term therapies. Thus, the development of new therapeutic approaches should consider multiple factors such as efficacy, dosing frequency, route of administration, toxicity as well as co-morbidities of patients. This article analyzes current challenges for the antipsoriatic drug development and reviews recent patent applications gathered from 2000 to 2011 for psoriasis treatment. Additionally, future perspectives for antipsoriatic drug development are summarized.     

Postoperative pain management: new,convenient analgesic therapies

Despite the potential benefits to patient health that can result from effective pain management, survey results continue to indicate that acute postoperative pain remains inadequately managed worldwide. The development of novel analgesics and advanced analgesic delivery techniques has the potential to improve current strategies for postoperative pain management. This article outlines the pharmacological principles and clinical utility of recently developed agents and a novel drug delivery device indicated for the management of moderate-to-severe acute postoperative pain.     

Opioid-induced bowel dysfunction: pathophysiology and potential new therapies

Opioid treatment for postoperative or chronic pain is frequently associated with adverse effects, the most common being dose-limiting and debilitating bowel dysfunction. Postoperative ileus, although attributable to surgical procedures, is often exacerbated by opioid use during and following surgery. Postoperative ileus is marked by increased inhibitory neural input, heightened inflammatory responses, decreased propulsive movements and increased fluid absorption in the gastrointestinal tract. The use of opioids for chronic pain is characterised by a constellation of symptoms including hard dry stools, straining, incomplete evacuation, bloating, abdominal distension and increased gastroesophageal reflux. The current management of opioid-induced bowel dysfunction among patients receiving opioid analgesics consists primarily of nonspecific ameliorative measures. Intensive investigations into the mode of action of opioids have characterised three opioid receptor classes -mu, delta and kappa- that mediate the myriad of peripheral and central actions of opioids. Activation of mu-opioid receptors in the gastrointestinal tract is responsible for inhibition of gut motility, whereas receptors in the central nervous system mediate the analgesic actions of opioids. Blocking peripheral opioid receptors in the gut is therefore a logical therapeutic target for managing opioid-induced bowel dysfunction. Available opioid antagonists such as naloxone are of limited use because they are readily absorbed, cross the blood-brain barrier, and act at central opioid receptors to reverse analgesia and elicit opioid withdrawal. Methylnaltrexone and alvimopan are recently developed opioid antagonists with activity that is restricted to peripheral receptors. Both have recently shown the ability to reverse opioid-induced bowel dysfunction without reversing analgesia or precipitating central nervous system withdrawal signs in non-surgical patients receiving opioids for chronic pain. In addition, recent clinical studies with alvimopan suggest that it may normalise bowel function without blocking opioid analgesia in abdominal laparotomy patients with opioid-related postoperative ileus.     

Postoperative pain management: new, convenient analgesic therapies

Despite the potential benefits to patient health that can result from effective pain management, survey results continue to indicate that acute postoperative pain remains inadequately managed worldwide. The development of novel analgesics and advanced analgesic delivery techniques has the potential to improve current strategies for postoperative pain management. This article outlines the pharmacological principles and clinical utility of recently developed agents and a novel drug delivery device indicated for the management of moderate-to-severe acute postoperative pain.     

Rheumatoid arthritis: an overview of new and emerging therapies

Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disorder characterized by symmetric inflammation of synovial joints leading to progressive erosion of cartilage and bone. The aim of treatment is to mitigate joint destruction, preserve function, and prevent disability. The American College of Rheumatology guidelines for the treatment of RA recommend that newly diagnosed patients with RA begin treatment with disease-modifying antirheumatic drugs (DMARDs) within 3 months of diagnosis. Methotrexate remains the most commonly prescribed DMARD and is the standard by which recent new and emerging therapies are measured. Increasing knowledge regarding the immunologic basis of RA and advances in biotechnology have resulted in new, targeted biological therapies against proinflammatory cytokines that have dramatically changed the treatment paradigm and outcomes of patients with RA. This article reviews the pharmacological rationale underlying RA therapy, with a focus on currently available biological therapies and new therapies in development.     

Management of cutaneous rosacea: emphasis on new medical therapies

Introduction: Over the past decade, both basic science and clinical research have provided new information on pathophysiology and therapy that has led to advances in the management of rosacea. As rosacea is a very common facial skin disorder in adults of both genders and essentially all races and ethnicities, these advances can provide therapeutic benefit to many affected individuals around the world.

Areas covered: This article provides a collective review of more recent information on the pathophysiology and clinical manifestations of rosacea, and discusses individual medical therapies based on PubMed literature searches on ‘rosacea’, ‘rosacea therapies’ and each therapy that are included in this article. The perspectives of the author on management of rosacea are also included. Newer therapies and treatment concepts received greater emphasis.

Expert opinion: Management of cutaneous rosacea involves patient education, integration of proper skin care, differentiation of visible manifestations and symptoms, selecting therapies that correlate with the manifestations that are to be treated, setting realistic patient expectations on anticipated degree and time course of response and designing an overall management plan that addresses needs of the individual patient. In many cases, a combination approach is needed, and due to the chronicity of the disease long-term management is often warranted.